In Principle:Proteins
are the products of genes. Proteins
catalyze biochemical reactions.
Such reactions produce phenotypes, either directly
or indirectly.
Different alleles produce
different phenotypesInteraction between alleles in
diploid organisms is
the subject matter of Genetics

Hypothesis:
"No-growth" phenotype results from a change in the genotype:
inability to synthesize amino acidis the result of loss of enzyme activity
each mutant corresponds to a defect in a particular enzyme:"One gene, one
enzyme" (Homework)
[ Remember: Beadle
& Tatum did not know about DNA in 1940 ]

1. In the above discussion, I have used "mutant" but carefully
avoided "mutation": WHY?

2. Critique the following statements:"arg- mutants result in defective
arginine.""arg- mutants are defects of
arginine.""arg- mutants are due to absence of
the gene for arginine.""arg- mutants are enzymes that block
synthesis of arginine."3.
Would you expect to observe an arg mutantclass with the following
phenotype? Explain.

Growth response to
added amino acids

mutant

none

ornithine

citrulline

arginine

arg-
X

-

+

-

+

Biochemical
Basis
of Human Genetic Diseases

In a haploid
organism, discovery of DNA shows nature
of metabolic "mutants":

Mutations
affect the genes responsible
for different enzymes: mutate
the gene eliminate (or modify) the enzymeWhat about diploid organisms? Diploid organisms have two alleles at each gene locus: one from each
parentInteractions between alleles at a
locus are the subject matter of genetics

PKU arises from
variation at the Phenylalanine Hydroxylase
(PAH)gene locusImportant: This
gene is not a gene "for" PKU: it is a gene "for" PAHDiploid humans each have two alleles at this locusAllelic variants produce
different levels of PAH activity
Consider three (hypothetical)
alleles: A, B,
& C :

Phenotypic consequences of
interactions between alleles at the PAH locus

Genotype

PAH Activity

[phe]
uM

PKU Phenotype

AA

100%

60

Standard

AB

30%

120

Standard

CC

5%

200 ~
300

Hyperphenylalanemia:
no special diet required

BB

0.3%

600
~ 2400

Classic PKU:
special diet required

[Alleles B
& C) arise fromDNA mutations in the PAH gene]PKU is a classic example of a "recessive" genetic disease: What does this mean?ABgenotype shows same PKU
phenotype as AA genotype
that is, A allele shows haplosufficiency:
one 'dose' is
sufficient to produce standard phenotype
or, expression
of A allele "masks" expression of B allele A is therefore "dominant"to B in
influencing PKU phenotypeB is therefore "recessive" to A butPAH activity phenotype of AB is intermediatebetween AA
& BBABphenotype
is closer to BBthan AA (0% < 30%<<100%)B is an "incomplete dominant" to A